Overactive dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. It has been hypothesized that prolonged exposure of catecholamine neurons to excessive levels of dopamine or to the oxidative metabolites of dopamine may produce neuronal damage, cell death, and be partially responsible for some of the negative symptoms of schizophrenia. Catecholamines have been shown to be neurotoxic to norepinephrine and dopamine neurons in primary culture (J Neurosci Res 26:428, 1990; J Pharmacol Exp Ther 262:1274, 1992). We are evaluating the neurotoxic effects of dopamine by using a clonal cell line developed by Chikaraishi and co-workers (J Neurosci 13:1280, 1993). This cell line was derived from a tyrosine hydroxylase positive tumor obtained from the CNS of transgenic mice carrying the SV 40 T antigen oncogene under the transcriptional control of the rat tyrosine hydroxylase gene. We found that incubation of CATH.a cells with dopamine produced dose-dependent cell death, with the highest concentration of dopamine (500 muM) killing 65% of the cells relative to untreated cells. We evaluated the possibility that the toxicity of dopamine is a receptor-mediated phenomenon by using a variety of D1 and D2 agonists and antagonists. Quinpirole, a selective D2 agonist was not neurotoxic, whereas incubation of CATH.a cells with D1 agonists (6-Bromo APA, SKF 38393) produced a dose-dependent cell death, with 84% of the cells dying at a concentration of 100 muM. Incubation of the cells with 10 muM of the selective D1 antagonists (SCH 23390, SKF 83566) produced no cell death. The concomitant treatment of the cells with D1 agonists (100 muM) and D1 antagonists (100 muM) partially prevented the neurotoxicity of the D1 agonists. These data support the hypothesis that dopamine is neurotoxic to catecholaminergic neurons and that this neurotoxicity is partially mediated by D1 receptors.